This project is attempting to determine the pharmacological consequences associated with the chronic administration of d- and 1-amphetamine to rodents. The development of pharmacological tolerance to the amphetamines will be studied in a variety of central and peripheral systems, and the biochemical mechanisms underlying this phenomena will be determined. While tolerance does not develop to amphetamine-enhanced spontaneous motor activity, we have demonstrated that this phenomenon exists with respect to d- and l-amphetamine-induced changes in low-frequency electroshock seizure threshold and pentylenetetrazol-induced minimal and maximal seizures in mice. We are presently studying the effects of the chronic administration of the amphetamine isomers on cardiovascular function in vivo (pithed rat) and in vitro (guinea pig atria) as well as neuromuscular transmission in vitro (rat phrenic nerve-diaphragm preparation). The results obtained in these studies will be correlated with the biochemical mechanisms responsible for the development of tolerance.